AIM To investigated the effects and potential mechanisms of pinacembrin on the cognitive function against Aβ-induced toxicity.METHODS Mice received an intracerebroventricular fusion of Aβ25-35.The behavioral performance, cerebral cortex neuropil ultrastructure, and neuronal degeneration were detected.The mechanism was conducted using fluorescence-based muhiparametric technologies on a high-content analysis platform.RESULTS Pinecembrin improved cognitive function, preserved ultrastructural neuropils and decreased neurodegeneration of cerebral cortex in Aβ25-35-treated mice.It did not provide sufficient effect on inhibiting Aβ1-42 production and scavenging intraeellular ROS, but significantly inhibited the upregulation of RAGE transcripts and protein expression.Further, pinocembrin depressed the activation of p38MAPK-MK2-HSP27 and SAPK/JNK-c-Jun pathways and the downstream NF-κB inflammatory response.It also alleviated mitochondrial dysfunction and regulated mitochondrion-mediated apoptosis.CONCLUSION Pinocembrin showed cognitive improvement in AD models.The mechanisms were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection.